1. Field of the Invention
The present invention relates to allergen vaccines, and more particularly to allergen vaccines that utilize fusion proteins in the treatment and prevention of allergic diseases.
2. Description of the Related Art
An allergy is an immune system reaction to a typically harmless substance. The immune system is always working to fight off parasites, fungi, viruses and bacteria. However, sometimes the immune system will treat a harmless substance (called an allergen) as an unwanted invader and try to fight it. This overreaction of the body's immune system to a typically harmless substance is called an allergic reaction.
Different allergies have different names, according to where they occur in the body. There are five common types of allergies, namely, allergic rhinitis, allergic dermatitis, asthma, food allergies and urticaria.
Allergic rhinitis affects the eyes, nose and sinuses. It causes stuffy or runny nose, ears and throat postnasal, watery or itchy eyes, and bronchial tube irritation, also known as hay fever. Allergic dermatitis affects the skin, causing an itchy rash. It is also known as contact dermatitis. Asthma affects the lungs, causing shortness of breath or wheezing. Food allergies affect the stomach and other internal organs, and may also cause symptoms to the entire body. Urticaria is a condition resulting with hives on the skin.
Almost anything can act as an allergen. However, some substances are very common allergens, such as, pollen and mold, dust mite droppings, pet allergens, food allergies, insect stings, and cockroach sensitivities. About a quarter of all Americans are genetically predisposed to allergic reactions from airborne pollen and mold. Dust mites, which are tiny spider-like creatures, leave droppings on bedsheets, pillows, and furniture. It is found that at least twenty million Americans are allergic to dust mite droppings, making it the next most common allergen. Around fifteen to thirty percent of people with allergies are found to be allergic to the third most popular allergens, pet allergens. They are sensitive to the proteins in pet dander (dead skin), pet saliva and pet urine. Those with dog allergies may be allergic to all dogs, or just certain breeds, but those with cat allergies are generally allergic to all cats. Cat allergies are about twice as common as dog allergies, affecting about six to ten million Americans.
Sensitivities to certain foods affect three to eight percent of children and one to two percent of adults. Ninety percent of all food allergies are caused by eight types of food, namely, milk, soy, eggs, wheat, peanuts, tree nuts, fish and shellfish. A few food preservatives also cause allergic reactions, namely, monosodium glutamate (found in many Asian foods, bouillon cubes and other preserved meat products) and metabisulfites (found in wines, particularly red wines). Insect stings from bees, wasps, fire ants, and the like, can be life threatening, and about two million Americans are prone to these allergic reactions. The toxins from the sting can cause severe reactions ranging from hives, wheezing, itching, swelling of the tongue, or even cardiac arrest. Cockroach sensitivies result when a cockroach crawls over food, or when cockroach droppings become airborne, and such allergens are ingested or inhaled, causing an allergic reaction. Anywhere from twenty-three to sixty percent of urban asthma sufferers are allergic to cockroach allergens.
It is important to realize that allergies are not only troublesome during the pollen season, but can be debilitating and become chronic disorders, which can have a negative long-term effect on one's health, pocketbook and happiness. Allergies should be taken seriously, and it is important to learn more about it.
Many allergies are passed onto children genetically through their parents. There is a one in three chance of developing some sort of allergy if the parent has the allergy (although not necessarily to the same allergen), according to the Asthma and Allergy Foundation of America. And if both parents have allergies, the child has a seventy percent chance of developing allergies. The substances that a person is allergic to depend on one's own genetic makeup, as well as one's exposure. Another factor is age. It was found that the peak age for developing an allergy seems to be around age nineteen.
One type of allergic reaction that requires special attention is anaphylaxis, which is sudden, severe, and potentially fatal, with symptoms that can affect various areas of the body. The symptoms usually appear very quickly after exposure to the allergen and can include intense itching all over the body, full-body swelling, respiratory distress, and can even lead to life threatening shock.
These reactions demand prompt medical attention and may require not only antihistamines and corticosteroids for relief, but also a form of adrenaline known as epinephrine. People who are highly susceptible to anaphylactic reactions should always carry a syringe of epinephrine with them and wear a medical alert bracelet.
A hallmark of the allergic diathesis is the tendency to maintain a persistent IgE response after antigen (allergen) presentation. The initial exposure to antigens stimulates the production of specific IgE molecules, which bind to high-affinity Fc receptors on the surface of mast cells. Upon reexposure of antigens, the cross-linking of antigens and membrane-bound IgE molecules result in the release of vasoactive mediators, setting off subsequent clinical manifestation of sneezing, pruritus, and bronchospasm. Immunoglobulin receptors (also referred to as Fc receptors), are cell-surface receptors of mast cells, that bind to the constant region of immunoglobulins, and mediate various immunoglobulin functions other than antigen binding.
Fc receptors that bind with IgE molecules (a type of immunoglobulin) are found on many types of cells in the immune system. There are two different Fc receptors currently known for IgE, the multichain high-affinity receptor, FcεRI, and the low-affinity receptor, FcεRII. IgE molecules mediate its biological responses as an antibody through these Fc receptors. The high-affinity FcεRI receptor, expressed on the surface of mast cells, basophils, and Langerhans cells, belongs to the immunoglobulin gene superfamily, and has a tetrametric structure composed of an α-chain, a β-chain and two disulfide-linked γ-chains that are required for receptor expression and signal transduction. The α-chains of the receptor interact with the distal portion of the third constant domain of the IgE heavy chain. The specific region of the human IgE molecule involved in binding to the human FcεRI receptor have been identified as including six amino acids, Arg-408, Ser-411, Lys-415, Glu-452, Arg-465, and Met-469. The interaction is highly specific with a binding constant of about 1010M−1.
The low-affinity FcεRII receptor, represented on the surface of inflammatory cells, such as eosinophils, leukocytes, B lymphocytes, and platelets, did not evolve from the immunoglobulin superfamily but has substantial homology with several groups of animals and is made up of a transmembrane chain with an intracytoplasmic NH2 terminus. The low-affinity receptor, FcεRII (CD23), is currently known to have two forms, FcεRIIa and FcεRIIb, both of which have been cloned and sequenced. The two forms differ only in the N-terminal cytoplasmic region, with the extracellular domains being identical. FcεRIIa is normally expressed on B cells, while FcεRIIb is expressed on T cells, B cells, monocytes and eosinophils upon induction by the cytokine IL-4.
Through the high-affinity FcεRI receptor, IgE plays key roles in an array of acute and chronic allergic reactions, including asthma, allergic rhinitis, atopic dermatitis, severe food allergies, chronic urticaria and angioedema, as well as the serious physiological condition of anaphylactic shock. The binding of a multivalent antigen to an antigen-specific IgE molecule, which is specifically bound to a FcεRI receptor on the surface of a mast cell or basophil, stimulates a complex series of signaling events that culminate in the release of host vasoactive and proinflammatory mediators that contributes to both acute and late-phase allergic responses.
The function of the low-affinity FcεRII receptor (also referred to as CD23), found on the surface of B lymphocytes, is less well-established than that of the FcεRI receptor. FcεRII, in a polymeric state, binds to IgE molecules, and this binding may play a role in controlling the type (class) of antibody produced by B cells.
Three groups of Fcγ receptors that bind to the constant region of human IgG molecules have so far been identified on cell surfaces. They are, FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), all of which belong to the immunoglobulin gene superfamily. The three Fcγ receptors have a large number of various isoforms.
In addition to the stimulatory FcεRI receptor, mast cells and basophils also co-express an immunoreceptor tyrosine-based inhibition motif (ITIM)-containing inhibitory low-affinity receptor, called the FcγRIIb receptor, which act to negatively regulate antibody functions. The FcγRIIb receptor belongs in the inhibitory receptor superfamily (IRS), which is a growing family of structurally and functionally similar inhibitory receptors that negatively regulate immunoreceptor tyrosine-based activation motif (ITAM)-containing immune receptors and a diverse array of other cellular responses. Coaggregation of an IRS member (such as FcγRIIb receptor) with an activating receptor (such as FcεRI receptor) leads to phosphorylation of the characteristic ITIM tyrosine and subsequent recruitment of the SH2 domain-containing protein tyrosine phosphatases SHP-1 and SHP-2, and the SH2 domain-containing phospholipases, SHIP and SHIP2. Possible outcomes of the coaggregation include inhibition of cellular activation, as demonstrated by the coaggregation of FcγRIIb and B-cell receptors, T-cell receptors, and activating receptors, such as FcεRI and cytokine.
A key contributor to asthma, allergic rhinitis and severe food reactions is the induced IgE-driven mediators released from mast cells and basophils. The cross-linking of a mast cell or basophil FcεRI receptor with a multivalent antigen, activates tyrosine phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the β- and γ-FcεRI subunit cytoplasmic tails, thereby initiating downstream signaling through Syk. Mast cells and basophils also express the FcγRIIb receptor, which contains a single conserved immunoreceptor tyrosine-based inhibition motif (ITIM) within its cytoplasmic tail. Studies indicate that the aggregating of FcγRIIb to FcεRI leads to rapid tyrosine phosphorylation of the FcγRIIb ITIM tyrosine by FcεRI-associated Lyn and inhibition of FcεRI signaling. This hypothesis has been supported in experiments using human Ig Fcγ-Fcε fusion proteins that directly cross-link the FcεRI and FcγRIIb receptors on human basophils.
Treatments of allergies include avoidance, immunotherapy, and allergy medications. The best course may simply be avoiding any allergens. Minimizing exposure can make a significant difference to allergy sufferers. However complete avoidance is not always possible.
Immunotherapy, also known as allergy shots, can help built allergy resistance. However immunotherapy is expensive and may take several years to take effect on the allergies. For most allergy sufferers, medications that treat allergy symptoms are a much better option.
Allergy medications can sometimes control the symptoms with over-the-counter or prescription medications. The treatment of allergy such as severe asthma is still a serious medical challenge. In addition, many of the therapeutics currently used in allergy treatment have serious side-effects. Common allergy medications include corticosteroids, steroid nasal sprays, antihistamines, decongestants, decongestants combined with antihistamines, cromolyn sodium and ipratropium bromide.
Doctors and allergy sufferers are anxiously awaiting the FDA to approve an Anti-IgE compound called omalizumab (brand name Xolair) for the treatment of allergic asthma. Omalizumab is the first anti-IgE drug submitted for FDA approval, although more are on the horizon.
Anti-IgE drugs are a breakthrough in allergy treatment for those with severe year-round allergies. Basically, the anti-body contained in anti-IgE drugs binds to the IgE circulating in the body after exposure to an allergen. This binding of the medication with the IgE prevents and the IgE from binding to mast cells and triggering mast cell rupture. The mast cells then remain intact, preventing the release of the histamine, prostaglandins and leukotrienes that cause allergy symptoms. In other words, instead of treating symptoms after they've already occurred. Anti-IgE drugs will prevent symptoms from occurring at all.
When approved, anti-IgE injections are expected to eventually replace traditional allergy immunotherapy injections. They offer a distinct advantage over traditional shots. Instead of doctors having to diagnose allergies precisely and administer specific solutions of those antibodies, anyone suffering from allergies can get a standard anti-IgE shot which will work to prevent allergic reactions, no matter what type. There are some side effects and very expensive.
Some prescription medications are avoidable to help control allergic rhinitis symptoms such as nasal steroids, antihistamines, and decongestants. But one of the newest forms of treatment for allergic rhinitis getting positive feedback are leukotrienses modifiers.
Leukotriene modifiers are not exactly new. But these drugs, originally approved to fight asthma, are proving effective in combating allergic rhinitis symptoms as well and are now being approved for that purpose.
Luekotriene modifier work by blocking the effects of leukotrienes, which are chemicals produced by certain cells in the body in response to an allergy. These leukotriene molecules contribute to the inflammation, swelling, airway constriction and production of mucus seen in allergic reactions. Leukotriene modifiers, which show a low incidence of side effects, are often prescribed in combination which steroids to prevent and treat allergy and asthma symptoms. In many cases, leukotriene modifiers help patients reduce their steroids dosage and help control symptoms such as itching, sneezing, wheezing and congestion.
Most US allergy sufferers who choose allergy immunotherapy treatment receive injections in their doctor's office. But an alternative therapy is getting good results in Europe. Instead of injections, allergy sufferers in France, Italy and Germany are prescribed allergen extract drops, which are concentrated dosages of the substance to which they are allergic, such as pollen. Allergy sufferers can place the drops under their tongue at home instead of visiting the doctor's office for shots.
The treatment is considered effective at controlling symptoms like wheezing, sneezing and runny noses that in Europe the French health care system use it for the treatment. Some American doctors are already using the drops system as well. But most American allergy sufferers will have to wait for FDA approval of the drops. The FDA is waiting for the results of ongoing studies of the drops before it initiates a formal review.
Although an anti-IgE antibody currently in clinical trials (rhuMAb-E26, Genentech, Inc.) and other experimental therapies such as antagonists of IL-4 show promising results, there is a need for the development of additional therapeutic strategies and agents to control allergic disease, such as asthma, severe food allergy, and chronic urticaria and angioedema.
One approach to the treatment of allergic diseases is by use of allergen-based immunotherapy. This methodology uses whole antigens as “allergy vaccine” and is now appreciated to induce a state of relative allergic tolerance. This technique for the treatment of allergy is frequently termed “desensitization” or “hyposensitization” therapy.
Increasing doses of allergic peptide are administered, typically by injection, to a subject over an extended period of time, frequently months or years. The mechanism of action of this therapy is thought to involve induction of IgG inhibitory antibodies, suppression of mast cell/basophil reactivity, the promotion of T-cell anergy, and/or clonal deletion, and in the long term, decrease in the levels of allergen specific IgE. The use of this approach is, however, hindered in many instances by poor efficacy and serious side effects including the risk of triggering a systemic and potentially fatal anaphylactic response, where the clinical administration of the allergen induces the severe allergic response it seeks to suppress. Thus, there exists a strong need to develop treatments for allergic diseases.